U.S. patent application number 11/572809 was filed with the patent office on 2008-01-03 for method for synthesis of 2,5-dioxane-1,4-diones.
This patent application is currently assigned to Societe de Conseils de Recherches et D'Applications Scientifiques. Invention is credited to Frederic Ben, Didier Bourissou, Roland Cherif-Cheikh, Magalie Graullier, Blanca Martin-Vaca, Martin Montes.
Application Number | 20080004453 11/572809 |
Document ID | / |
Family ID | 34947240 |
Filed Date | 2008-01-03 |
United States Patent
Application |
20080004453 |
Kind Code |
A1 |
Bourissou; Didier ; et
al. |
January 3, 2008 |
Method for Synthesis of 2,5-Dioxane-1,4-Diones
Abstract
The invention relates to a novel method for the synthesis of
2,5-dioxane-1,4-diones having formula (I), comprising the oxidation
of the ketone function of a cyclic compound having formula (II),
wherein R.sub.1, R.sub.2, R.sub.3 and R.sub.4 independently
represent the hydrogen atom, halo, (C.sub.2-C.sub.6) alkenyl,
(C.sub.3-C.sub.7)cycloalkyl, cyclohexenyl and a radical having
formula --(CH.sub.2).sub.m--V--W. ##STR1##
Inventors: |
Bourissou; Didier;
(Plaisance Du Touch, FR) ; Martin-Vaca; Blanca;
(Toulouse, FR) ; Ben; Frederic; (Toulouse, FR)
; Graullier; Magalie; (Toulouse, FR) ;
Cherif-Cheikh; Roland; (Castelldefels, ES) ; Montes;
Martin; (Saint Quirze Del Valles, ES) |
Correspondence
Address: |
HUNTON & WILLIAMS LLP;INTELLECTUAL PROPERTY DEPARTMENT
1900 K STREET, N.W.
SUITE 1200
WASHINGTON
DC
20006-1109
US
|
Assignee: |
Societe de Conseils de Recherches
et D'Applications Scientifiques
Paris Cedex 16
FR
|
Family ID: |
34947240 |
Appl. No.: |
11/572809 |
Filed: |
July 25, 2005 |
PCT Filed: |
July 25, 2005 |
PCT NO: |
PCT/FR05/01909 |
371 Date: |
January 26, 2007 |
Current U.S.
Class: |
549/274 |
Current CPC
Class: |
C07D 319/12
20130101 |
Class at
Publication: |
549/274 |
International
Class: |
C07D 319/10 20060101
C07D319/10 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 26, 2004 |
FR |
0408211 |
Claims
1. Process for the preparation of 2,5-dioxane-1,4-diones of formula
(I) ##STR11## in which R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are,
independently, a hydrogen atom; halo; (C.sub.2-C.sub.6) alkenyl;
(C.sub.3-C.sub.7) cycloalkyl; cyclohexenyl; or a radical of formula
--(CH.sub.2).sub.m--V--W; wherein V is a covalent bond, an oxygen
atom or a --C(O)--O-- radical; represents is a hydrogen atom, a
(C.sub.1-C.sub.18) alkyl radical optionally substituted by one or
more identical or different halo radicals; an aryl or aralkyl
radical, the aryl and aralkyl radicals being optionally substituted
by one or more identical or different substituents including:
--(CH.sub.2).sub.n--Y-Z, halo, nitro or cyano; Y is --O--, --S-- or
a covalent bond; Z is a hydrogen atom or a (C.sub.1-C.sub.6) alkyl
radical optionally substituted by one or more identical or
different halo radicals; or aralkyl; m and n are independently an
integer from 0 to 4; comprising oxidizing the ketone function of a
cyclic compound of formula (II) ##STR12## in which R.sub.1,
R.sub.2, R.sub.3 and R.sub.4 are defined above.
2. Preparation process according to claim 1, wherein the process is
carried out in the presence of an oxidizing agent.
3. Preparation process according to claim 2, wherein the oxidizing
agent is used in the presence of a catalyst.
4. Preparation process according to claims 2 or 3, wherein the
oxidizing agent is a peracid or a peroxide.
5. Preparation process according to claim 2, wherein the oxidizing
agent is a peracid.
6. Preparation process according to claim 5, wherein the oxidizing
agent is used in the presence of a Lewis acid or a strong acid.
7. Preparation process according to claim 6, wherein the oxidizing
agent used in the presence of a strong acid includes sulphonic
acids.
8. Preparation process according to claim 5, wherein the oxidizing
agent is metachloroperbenzoic acid.
9. Preparation process according to claim 8, wherein the oxidizing
agent is used in the presence of trifluoromethanesulfonic acid.
10. Preparation process according to claim 2, wherein the oxidizing
agent is a peroxide.
11. Preparation process according to claim 1, wherein the aryl
radical is a phenyl radical and the aralkyl radical is a benzyl
radical.
12. Preparation process according to claim 1, wherein R.sub.1,
R.sub.2, R.sub.3 and R.sub.4 are, independently, a hydrogen atom or
a radical of formula --(CH.sub.2).sub.m--V--W, wherein V is a
covalent bond and W is a (C.sub.1-C.sub.6) alkyl radical.
13. Preparation process according to claim 1 wherein R.sub.1,
R.sub.2, R.sub.3 and R.sub.4 are, independently, a hydrogen atom, a
methyl or ethyl radical.
14. Preparation process according to claim 1, wherein R.sub.1 and
R.sub.2 are, independently, a radical of formula
--(CH.sub.2).sub.m--V--W, wherein V is a covalent bond, m=0 and W
is a (C.sub.1-C.sub.6) alkyl radical, and R.sub.3 and R.sub.4 are,
independently, a hydrogen atom or a radical of formula
--(CH.sub.2).sub.m--V--W, wherein V is a covalent bond, m=0 W is a
(C.sub.1-C.sub.6) alkyl radical.
15. Preparation process according to claim 1, wherein R.sub.1 and
R.sub.2 are, independently, a methyl or ethyl radical, and R.sub.3
and R.sub.4 are, independently, a hydrogen atom, a methyl or ethyl
radical.
Description
[0001] The present invention relates to a novel method for the
synthesis of 2,5-dioxane-1,4-diones.
[0002] PLGAs are generally obtained by ring-opening
(co)polymerization of lactide and glycolide. These monomers derived
from lactic acid and glycolic acid are the prototypes of
2,5-dioxane-1,4-diones. Modification of the properties of the PLGAs
is of great importance, in particular in their use as a
biodegradable and bioassimilable matrix for the trapping and
controlled release of active ingredients. Somewhat surprisingly,
the approach which consists of modifying the substituents of the
2,5-dioxane-1,4-dione backbone has only been slightly developed up
to the present, which can in practice be explained by the somewhat
low accessibility of these units. ##STR2##
[0003] Symmetrical monomers such a lactide or glycolide are
generally prepared from the corresponding .alpha.-hydroxy acids.
This approach is difficult as it requires the elimination of the
water formed and the distillation under vacuum of the monomer. In
order to access asymmetrical monomers, two different precursors
must be used, typically an .alpha.-hydroxy acid and a mono- or
di-halogenated derivative (C.-M. Dong et al., J. Polym. Sci. Part
A: Polym. Chem. 2000, 38, 4179-4184; M. Leemhuis et al., Eur. J.
Org. Chem. 2003, 3344-3349). ##STR3##
[0004] In practice, the major limitation of all these synthesis
strategies is probably the final stage of closing the ring with 6
members which is inherently in competition with the formation of
dimers and oligomers, by intermolecular rather than intramolecular
route. The applicant has therefore envisaged a novel synthesis
route for 2,5-dioxane-1,4-diones.
[0005] As subject of the present invention is therefore a process
for preparing 2,5-dioxane-1,4-diones of formula (I) ##STR4##
[0006] in which R.sub.1, R.sub.2, R.sub.3 and R.sub.4 represent,
independently, the hydrogen atom; halo; (C.sub.2-C.sub.6)alkenyl;
(C.sub.3-C.sub.7)cycloalkyl; cyclohexenyl; a radical of formula
--(CH.sub.2).sub.m--V--W [0007] V represents a covalent bond, the
oxygen atom or the --C(O)--O-- radical; [0008] W represents the
hydrogen atom, a (C.sub.1-C.sub.18)alkyl radical optionally
substituted by one or more identical or different halo radicals;
the aryl or aralkyl radical, the aryl and aralkyl radicals being
optionally substituted by one or more identical or different
substituents chosen from: --(CH.sub.2).sub.n--Y-Z, halo, nitro and
cyano; [0009] Y represents --O--, --S-- or a covalent bond; [0010]
Z represents the hydrogen atom or a (C.sub.1-C.sub.6)alkyl radical
optionally substituted by one or more identical or different halo
radicals; or aralkyl; [0011] m and n represent independently an
integer from 0 to 4;
[0012] by oxidation of the ketone function of a cyclic compound of
formula (II) ##STR5##
[0013] In the definitions indicated above, the expression halo
represents the fluoro, chloro, bromo or iodo radical, preferably
chloro, fluoro or bromo. The expression (C.sub.1-C.sub.6)alkyl
represents a linear or branched alkyl radical having from 1 to 6
carbon atoms, such as the methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, sec-butyl and tert-butyl, pentyl or amyl, isopentyl,
neopentyl, 2,2-dimethyl-propyl, hexyl, isohexyl or
1,2,2-trimethyl-propyl radicals. The term (C.sub.1-C.sub.18)alkyl
designates a linear or branched alkyl radical having 1 to 18 carbon
atoms, such as the radicals containing from 1 to 6 carbon atoms as
defined above but also heptyl, octyl, 1,1,2,2-tetramethyl-propyl,
1,1,3,3-tetramethyl-butyl, nonyl, decyl, undecyl, dodecyl,
tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl.
By the expression alkyl substituted by at least one radical halo is
meant any linear or branched alkyl chain, containing at least one
radical halo positioned along the chain such as for example
--CHCl--CH.sub.3 but also --CF.sub.3.
[0014] In the present Application also, the (CH.sub.2).sub.i
radical (i being an integer which can represent m and n as defined
above), represents a linear or branched hydrocarbonated chain, of i
carbon atoms. Thus the --(CH.sub.2).sub.3-- radical can represent
--CH.sub.2--CH.sub.2--CH.sub.2-- but also
--CH(CH.sub.3)--CH.sub.2--, --CH.sub.2--CH(CH.sub.3)-- or
--C(CH.sub.3).sub.2--.
[0015] By (C.sub.2-C.sub.6)alkenyl, is meant a linear or branched
alkyl radical containing from 2 to 6 carbon atoms and having at
least one unsaturation (double bond), such as for example vinyl,
allyl, propenyl, butenyl or pentenyl.
[0016] The term (C.sub.3-C.sub.7)cycloalkyl designates a saturated
carbon monocyclic system comprising from 3 to 7 carbon atoms, and
preferably the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or
cycloheptyl rings.
[0017] The expression aryl represents an aromatic radical,
constituted by a condensed ring or rings, such as for example the
phenyl, naphthyl, fluorenyl or anthryl radical. The term aralkyl
(arylalky) preferably designates the radicals in which the aryl and
alkyl radicals are as defined above such as for example benzyl or
phenethyl.
[0018] Thus, during the conversion process of compound (II) to
compound (I) ##STR6##
[0019] the competitive dimerization and oligomerization reactions
which are observed during the synthesis of lactide or glycolide by
condensation, are completely avoided.
[0020] For conversion of the ketone function of compound (II) to an
ester function, several types of oxidation can be utilized; the
oxidation can thus be carried out for example in the presence of an
oxidizing agent such as a peracid or a peroxide (according to the
Baeyer Villiger oxidation reaction), in the presence of a metallic
catalyst (S. I. Murahashi et al., Tetrahedron Lett. 1992, 33,
7557-7760 and C. Bolm et al., Tetrahedron Lett. 1993, 34,
3405-3408) or by enzymatic route (M. D. Mihovilovic et al., Eur. J.
Org. Chem. 2002, 3711-3730).
[0021] Preferably, a process according to the invention is carried
out in the presence of an oxidizing agent according to the Baeyer
Villiger oxidation reaction. In this case, the oxidation reaction
is carried out very preferentially on the more encumbered side of
the ketone in such a manner that 2,5-dioxane-1,4-diones can be
obtained very selectively. In a preferable way, the oxidizing agent
is used in the presence of a catalyst.
[0022] The oxidizing agent (or oxidation agent) used for
implementing the process according to the invention, can be a
peracid or a peroxide. As an example of a peracid, there can be
mentioned trifluoroperacetic acid (TFPAA), peracetic acid (PAA),
metachloroperbenzoic acid (m-CPBA), preferably in combination with
Lewis acids (SnCL.sub.4, Sn(OTf).sub.3, Re(OTf).sub.3) or strong
acids (sulphonic acids, Nafion-H, CF.sub.3COOH etc.). As an example
of a peroxide, there can be mentioned hydrogen peroxide
(H.sub.2O.sub.2); the hydrogen peroxide is used alone or in the
presence of a catalyst which can be a Lewis acid (such as BF.sub.3)
or a metallic complex either in homogeneous phase (Mo, Re, Pt) or
in heterogeneous phase (tin zeolite, tin hydrotalcite); there can
also be mentioned bis(trimethylsilyl)peroxide
Me.sub.3SiOOSiMe.sub.3 which is used in the presence of a Lewis
acid (Me.sub.3SiOTf, SnCl.sub.4 or BF.sub.3.OEt.sub.2).
[0023] A more particular subject of the present invention is a
process as defined above, characterized in that the oxidation agent
is a peracid or a peroxide.
[0024] Preferably, the oxidizing agent is a peracid. The peracid is
preferably used in the presence of a Lewis acid or a strong acid,
and more particularly in presence of a strong acid selected from
sulphonic acids.
[0025] More preferably the peracid is metachloroperbenzoic acid
(m-CPBA). The metachloroperbenzoic acid is preferably used in the
presence of trifluoromethanesulfonic acid.
[0026] Preferably also, the oxidizing agent is a peroxide.
[0027] The oxidation agents mentioned above are in general
commercially available. The non-commercial agents can be
synthesized according to methods known to a person skilled in the
art. Thus, trifluoroperacetic acid which is not commercial can be
easily obtained by the action of hydrogen peroxide H.sub.2O.sub.2
on trifluoroacetic acid or anhydride CF.sub.3CO.sub.2H and
(CF.sub.3CO).sub.2O respectively (R. Liotta et al., J. Org. Chem.
1980, 45, 2887-2890; M. Anastasia et al., J. Org. Chem. 1985, 50,
321-325; P. A. Krasutsky et al., J. Org. Chem. 2001, 66,
1701-1707). Similarly, bis(trimethylsilyl)peroxide is not
commercially available but it is easily accessible from the
H.sub.2O.sub.2-1,4-diazabicyclo[2,2,2]octane [DABCO,
N(CH.sub.2CH.sub.2).sub.3N] and Me.sub.3SiCl complex (P. G. Cookson
e al., J. Organomet. Chem. 1975, 99, C31-C32; M. Taddei et al.,
Synth. Comm. 1986, 633-635).
[0028] The cyclic keto-esters of formula (II), used as precursors
for the synthesis of 2,5-dioxane-1,4-diones (I) as defined above,
are easily accessible by standard methods known to a person skilled
in the art (E. B. Reid et al., J. Org. Chem. 1950, 15,
572-582).
[0029] A more particular subject of the present invention is also a
process as defined above, characterized in that the aryl radical is
the phenyl radial and the aralkyl radical is the benzyl
radical.
[0030] A more particular subject of the present invention is also a
process as defined above, characterized in that R.sub.1, R.sub.2,
R.sub.3 and R.sub.4 represent, independently, the hydrogen atom; or
a radical of formula --(CH.sub.2).sub.m--V--W with V which
represents a covalent bond and W a (C.sub.1-C.sub.6)alkyl radical,
and preferably R.sub.1, R.sub.2, R.sub.3 and R.sub.4 represent,
independently, the hydrogen atom, the methyl radical or the ethyl
radical.
[0031] A more particular subject of the present invention is also a
process as defined above, characterized in that R.sub.1 and R.sub.2
represent, independently, a radical of formula
--(CH.sub.2).sub.m--V--W with V which represents a covalent bond,
m=0 and W a (C.sub.1-C.sub.6)alkyl radical, and R.sub.3 and R.sub.4
represent, independently, the hydrogen atom or a radical of formula
--(CH.sub.2).sub.m--V--W with V which represents a covalent bond,
m=0 and W a (C.sub.1-C.sub.6)alkyl radical.
[0032] A more particular subject of the present invention is also a
process as defined above, characterized in that R.sub.1 and R.sub.2
represent, independently, the methyl or ethyl radical, and R.sub.3
and R.sub.4 represent, independently, the hydrogen atom, the methyl
or ethyl radical.
[0033] A subject of the present invention is also compounds of
formula (I) as obtained according to the method defined above.
[0034] Experimental Part
EXAMPLE 1
3,3-dimethyl-2,5-dioxane-1,4-dione
Stage 1: Synthesis of the Precursor (II)
[0035] The synthesis of compound (II) is carried out according to
the following reaction diagram: ##STR7##
[0036] The formation of compound (2) from compound (1) can be
carried out according to H. C. Brown et al., J. Am. Chem. Soc.
1988, 110, 1539-1546. The synthesis stages of compounds (3) and (4)
can be carried out according to M. Conrad et al., Ber. 1898, 31,
2726-2731. Finally, the final stage of formation of compound (II)
from compound (4) can be carried out according to E. B. Reid et
al., J. Org. Chem. 1950, 15, 572-582.
Stage 2: Synthesis of 3,3-dimethyl-2,5-dioxane-1,4-dione
[0037] ##STR8##
[0038] Conditions 1:
[0039] A solution of 5 g of cyclic keto-ester (39 mmol) and 13.5 g
of metachloropebenzoic acid (2 eq.) in 100 ml of dichloromethane is
heated under reflux for 48 hours. NMR .sup.1H monitoring of an
aliquot of the reaction medium reveals the complete conversion of
the ring with 5 members and the formation of mostly
3,3-dimethyl-2,5-dioxane-1,4-dione (spectroscopic yield: 85%).
[0040] Conditions 2:
[0041] A solution of 5 g of cyclic keto-ester (39 mmol) and 8.1 g
of metachloroperbenzoic acid (1.2 eq.) in 40 ml of dichloromethane
is heated under reflux for 24 hours. The complete conversion of the
ring with 5 members is monitored by NMR .sup.1H on a sample. The
reaction medium is then cooled down to -18.degree. C. overnight
then filtered on frit in order to eliminate the metachlorobenzoic
acid formed. The filtrate is concentrated under vacuum. The residue
is recrystallized from ethyl acetate at -18.degree. C. 3.9 g of
analytically pure, 3,3-dimethyl-2,5-dioxane-1,4-dione are thus
obtained (70% of isolated product yield). The product is
characterized by NMR .sup.1H [4.97 (s, 2H), 1.70 (s, 6H)] and
.sup.13C [167.7 and 163.9 (C.dbd.O), 79.8 (C.sub.q), 65.8
(CH.sub.2), 25.8 (CH.sub.3)], RX (cf. FIG. 1), mp (84-85.degree.
C.) and elementary analysis. Calculated C: 50.00, H: 5.56; Found C:
49.98, H: 5.33.
[0042] Conditions 3:
[0043] A solution of 1 g of cyclic keto-ester (7.8 mmol), 2.7 g of
metachloroperbenzoic acid (2 eq.) and 70 .mu.l of
trifluoromethanesulphonic acid (0.1 eq.) in 20 ml of
dichloromethane is left under stirring at ambient temperature for 3
hours. The solvent is eliminated under vacuum, then the medium is
analyzed. NMR .sup.1H reveals the complete conversion of the ring
with 5 members and the formation of mostly
3,3-dimethyl-2,5-dioxane-1,4-dione (spectroscopic yield: 60%).
EXAMPLE 2
3-ethyl-3-methyl-2,5-dioxane-1,4-dione
Stage 1: Synthesis of Precursor (II)
[0044] The synthesis of compound (II) is carried out according to
the same reaction diagram as in Example 1: ##STR9##
Stage 2: Synthesis of 3-ethyl-3-methyl-2,5-dioxane-1,4-dione
[0045] ##STR10##
[0046] A solution of 0.5 g of cyclic keto-ester (3.5 mmol) and 1.21
g of metachloroperbenzoic acid (2 eq.) in 10 ml of dichloromethane
is heated under reflux for 48 hours. After returning to ambient
temperature, the solvent is eliminated under vacuum. NMR .sup.1H
analysis reveals the complete conversion of the ring with 5 members
and the formation of mostly 3-ethyl-3-methyl-2,5-dioxane-1,4-dione
(spectroscopic yield: 75%). NMR .sup.1H characteristics [4.97 (s,
2H), 1.95 (q, 2H, .sup.3J.sub.HH=7.5 Hz), 1.67 (s, 3H), 1.03 (t,
3H, .sup.3J.sub.HH=7.5 Hz)]. TABLE-US-00001 TABLE 1
Crystallographic data of the compound of the example 1. Empirical
formula C6 H8 04 Molar mass 144.12 Temperature 193(2) K Wavelength
0.71073 .ANG. Crystalline system Orthorhombic Space group
P2(1)2(1)2(1) Lattice parameters a = 5.8935(10) .ANG. .alpha. =
90.degree.. b = 9.6410(16) .ANG. .beta. = 90.degree.. c =
11.6372(19) .ANG. .gamma. = 90.degree.. Volume 661.22(19)
.ANG..sup.3 Z 4 Density (calculated) 1.448 Mg/m.sup.3 Absorption
coefficient 0.123 mm.sup.-1 F(000) 304 Crystal size 0.2 .times. 0.2
.times. 0.6 mm.sup.3 Theta values for data acquisition from 2.74 to
26.38.degree.. Values of the indices h, k, l -7 <= h <= 4,
-12 <= k <= 12, -14 <= 1 <= 14 Collected reflections
4337 Independent reflections 1346 [R(int) = 0.0559] Coll./the. data
ratio up to theta 100.0% 26.38.degree. Absorption correction None
Refinement method Full matrix least squares on F.sup.2
Data/constraints/parameters 1346/0/93 Correlation coefficient on
F.sup.2 1.070 Final R indices [I > 2sigma(I)] R1 = 0.0308, wR2 =
0.0742 R indices (all data) R1 = 0.0364, wR2 = 0.0774 Absolute
structural parameter 0.2(12) Max and min residual elec. density
0.182 and -0.144 e..ANG..sup.-3
[0047] TABLE-US-00002 TABLE 2 Atomic coodinates (.times.10.sup.4)
and equivalent isotropic displacement parameters (.ANG..sup.2
.times. 10.sup.3). U(eq) is defined as one-third trace of the
orthogonalized tensor U.sup.ij of the compound of the example 1. x
y z U(eq) C(1) 1812(2) 3446(2) 10097(1) 25(1) O(1) 2005(2) 3662(1)
11125(1) 32(1) C(2) 1817(3) 2391(2) 8227(1) 30(1) O(2) 1915(2)
2288(1) 9464(1) 28(1) C(3) 320(3) 3535(2) 7795(1) 28(1) O(3)
-557(2) 3507(1) 6861(1) 39(1) C(4) 1500(2) 4820(2) 9471(1) 26(1)
O(4) -18(2) 4628(1) 8487(1) 29(1) C(5) 3794(3) 5354(2) 9049(1)
35(1) C(6) 310(3) 5865(2) 10226(1) 37(1)
[0048] TABLE-US-00003 TABLE 3 Bond lengths [.ANG.] and bond angles
[.degree.] of the compound of the example 1. C(1)--O(1) 1.2047(17)
C(1)--O(2) 1.3391(19) C(1)--C(4) 1.523(2) C(2)--O(2) 1.4435(16)
C(2)--C(3) 1.499(2) C(3)--O(3) 1.2033(18) C(3)--O(4) 1.3412(19)
C(4)--O(4) 1.4643(18) C(4)--C(6) 1.510(2) C(4)--C(5) 1.528(2)
O(1)--C(1)--O(2) 119.12(14) O(1)--C(1)--C(4) 123.02(14)
O(2)--C(1)--C(4) 117.85(12) O(2)--C(2)--C(3) 114.11(12)
C(1)--O(2)--C(2) 119.30(12) O(3)--C(3)--O(4) 119.77(15)
O(3)--C(3)--C(2) 122.60(14) O(4)--C(3)--C(2) 117.63(12)
O(4)--C(4)--C(6) 104.80(12) O(4)--C(4)--C(1) 109.75(12)
C(6)--C(4)--C(1) 110.98(13) O(4)--C(4)--C(5) 109.40(12)
C(6)--C(4)--C(5) 111.91(14) C(1)--C(4)--C(5) 109.88(12)
C(3)--O(4)--C(4) 118.55(12)
[0049] TABLE-US-00004 TABLE 4 Anisotropic displacement parameters
(.ANG..sup.2 .times. 10.sup.3) of the compound of the example 1.
The anisotropic displacement factor exponent takes the form:
-2.pi..sup.2[h.sup.2 a*.sup.2U.sup.11 + . . . + 2 h k a* b*
U.sup.12] U.sup.11 U.sup.22 U.sup.33 U.sup.23 U.sup.13 U.sup.12
C(1) 16(1) 33(1) 26(1) 2(1) -1(1) 0(1) O(1) 29(1) 45(1) 23(1) 5(1)
-2(1) 2(1) C(2) 33(1) 33(1) 24(1) -3(1) 0(1) 1(1) O(2) 30(1) 29(1)
25(1) 2(1) -2(1) 2(1) C(3) 25(1) 36(1) 23(1) 3(1) 0(1) -5(1) O(3)
44(1) 48(1) 25(1) 0(1) -8(1) -2(1) C(4) 25(1) 30(1) 23(1) 1(1)
-4(1) 0(1) O(4) 30(1) 30(1) 27(1) 2(1) -7(1) 3(1) C(5) 33(1) 36(1)
34(1) 3(1) -2(1) -10(1) C(6) 41(1) 36(1) 35(1) -4(1) -3(1) 9(1)
[0050] TABLE-US-00005 TABLE 5 Coordinates of the hydrogen atoms
(.times.10.sup.4) and isotropic displacement parameters
(.ANG..sup.2 .times. 10.sup.3) of the compound of the example 1. x
y z U(eq) H(2A) 1262 1499 7913 36 H(2B) 3372 2540 7930 36 H(5A)
4514 4648 8565 52 H(5B) 4770 5554 9710 52 H(5C) 3570 6203 8600 52
H(6A) 58 6723 9792 56 H(6B) 1252 6064 10900 56 H(6C) -1153 5487
10476 56
* * * * *